Search Results (29,562)

Acute lung injury (ALI) is a common clinical acute respiratory disorder driven primarily by a diffuse pulmonary inflammatory response. Cordycepin (COR) is a bioactive metabolite extracted from the fungus Cordyceps militaris, which possesses antioxidant and anti-inflammatory properties. However, its underlying molecular mechanism remains to be elucidated. This study evaluated the therapeutic effect of COR on ALI and the underlying molecular mechanisms. MH-S cells were primed with lipopolysaccharide (LPS) at 1 µg/mL for 24 h and then treated with varying doses of COR for an additional 24 h. WB and RT-qPCR analyses showed that COR inhibited the phosphorylation of TGF-β-activated kinase 1 (TAK1) as well as the key kinases in the MAPK and NF-κB pathways in LPS-induced MH-S cells, as evidenced by decreased TAK1, p38, JNK, IκB-α and P65 expression levels, as well as decreased TNF-α, IL-6, IL-1β, MAP3K7, MAPK8 and MAPK14 relative expression. Six-week-old BALB/c mice were intranasally instilled with LPS at 3 mg/kg, followed 24 h later by oral gavage administration of various concentrations of COR. The results showed that COR can effectively suppress the progression of pulmonary tissue injury; similarly, the expression levels of key proteins and inflammatory factors in the TAK1-MAPK and NF-κB signaling pathways were downregulated. In summary, COR exerts a therapeutic effect on ALI by directly targeting TAK1 to inhibit the activation of the MAPK and NF-κB signaling pathways and concurrently suppressing key inflammatory cytokines. Full article

Background: Despite advances in prostate cancer (PC) radiotherapy, including intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic body radiotherapy (SBRT), genitourinary (GU) and gastrointestinal (GI) toxicities remain important complications. Identifying reliable predictors is essential for personalized treatment. Objective: The aim of this study was to summarize current evidence on clinical, dosimetric, immunological, and genetic predictors of acute and late GU and GI toxicities after PC radiotherapy. Materials and Methods: A structured literature review of studies published between 2000 and 2026 was conducted using PubMed, Scopus, and Europe PMC. Eligible studies included clinical investigations, randomized controlled trials, meta-analyses, and reviews assessing toxicity according to RTOG and/or CTCAE criteria. Results: GU toxicity was associated with pretreatment International Prostate Symptom Score (IPSS), large prostate volume, prior TURP, smoking, alpha-blocker use, and bladder/urethral dose. GI toxicity correlated with rectal dose–volume parameters, anorectal irradiation, anticoagulant therapy, and cardiovascular comorbidities. Acute grade ≥ 2 toxicity predicts late toxicity. Preliminary data from small single-center cohorts associate elevated IL-6, TGF-β1, TNF-α, and systemic immune-inflammation index with higher toxicity risk, and higher lymphocyte counts with lower risk; these findings require prospective validation. The PROSTOX radiogenomic signature is promising for the prediction of late GU toxicity but still requires independent external validation in larger, ethnically diverse cohorts with longer follow-up, and is not currently suitable for routine clinical decision-making. Conclusions: GU and GI toxicities have distinct predictive profiles. Integrating clinical, dosimetric, immunological, and genetic factors may improve personalized radiotherapy, although prospective multicenter validation remains necessary. Full article

A high-fat diet (HFD) promotes lipid metabolic disorders, chronic low-grade inflammation and skeletal muscle dysfunction. Kukoamine B (KB), a Lycium-derived polyamine alkaloid with reported anti-inflammatory and antioxidant activities, may protect against HFD-associated muscle impairment. C57BL/6J mice were fed an HFD and orally administered KB for 12 weeks. Muscle function was evaluated using inverted grid, forelimb grip strength and treadmill exhaustion tests. Histological, transcriptomic, ELISA, immunofluorescence and Western blot analyses were used to assess muscle injury and inflammatory signalling. KB reduced intramuscular lipid deposition, collagen accumulation and myofibre damage, improved muscle strength and exercise endurance, and partially restored AKT/mTOR-associated protein metabolic signalling. Transcriptomic analysis showed that KB downregulated HFD-activated inflammatory responses, chemokine signalling, lipopolysaccharide responses and Toll-like receptor-related pathways. KB also reduced plasma and skeletal muscle LPS levels, inhibited TLR4/MyD88/NF-κB signalling, and decreased TNF-α and IL-1β expression. TAK-242 mimicked the anti-inflammatory and muscle function-improving effects of KB, whereas their combination produced no statistically detectable additional effect under the conditions tested. These findings suggest that KB attenuates HFD-induced skeletal muscle dysfunction, potentially involving reduced LPS burden and suppression of TLR4/NF-κB-mediated metabolic inflammation. Full article

Background/Objectives: Chronic metabolic inflammation is associated with pro-inflammatory macrophage activation and mitochondrial dysfunction. Semaglutide, a widely used GLP-1 receptor agonist, has been reported to possess systemic anti-inflammatory properties, but its action on human macrophages, especially in the context of mitochondrial regulation, remains poorly understood. The aim of the study was to evaluate the direct effect of semaglutide on macrophage polarization and to investigate the roles of cAMP signaling and mitochondrial regulation in this process. Methods: THP-1 and U-937 monocytic cell lines were differentiated into macrophages and polarized into the M1-like phenotype using LPS/IFN-γ. Cells were treated with 100 nM semaglutide in the presence or absence of the adenylyl cyclase inhibitor SQ22536. Intracellular cAMP levels, mRNA expression of macrophage markers and key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), and levels of pro- and anti-inflammatory cytokines were determined. The COX-1/SDH-A and mtDNA/nDNA ratios were analyzed as markers of mitochondrial biogenesis. Results: Semaglutide induced cAMP accumulation in M0- and M1-like macrophages derived from both cell lines. This response was significantly attenuated by GLP-1R antagonist exendin(9–39), supporting the presence of functional GLP-1R signaling. Semaglutide supplementation during inflammatory polarization resulted in reduced levels of pro-inflammatory markers (CD80/CD86, TNF-α, IL-6) and increased expression of M2-associated genes CD206 and CD163 and secretion of the anti-inflammatory cytokine IL-10. Semaglutide also increased SIRT1 and PGC-1α expression, the COX-1/SDH-A ratio, and the mtDNA/nDNA ratio, suggesting activation of processes associated with mitochondrial biogenesis. All of the effects of semaglutide described above were attenuated by SQ22536, supporting an important contribution of cAMP signaling to these responses. Conclusions: Semaglutide acts directly on human monocytic cell line-derived macrophages, attenuating the M1-like program and promoting a shift toward a less inflammatory phenotype. These effects strongly depend on cAMP signaling and are accompanied by increased expression of SIRT1 and PGC-1α and mitochondrial changes consistent with enhanced biogenesis. Full article

Immune mediators are elevated due to carbon monoxide (CO) poisoning but their role in the development of neurological deficits is unknown. Circulating microparticles (MPs) are elevated in response to CO and correlate with the development of neurological complications. We hypothesized that interleukin (IL)-1β is carried by MPs and contributes to the development of neurological sequelae (NS). Blood-borne IL-1β in CO-poisoned patients is almost exclusively carried by MPs. Healthy humans have 0.8 ± 0.8 (n = 27) MPs/μL bearing IL-1β on the membrane surface. IL-1β-bearing MPs obtained from patients at the time of CO poisoning diagnosis who recover (Global Deterioration Score [GDS] = 1 at 1 month) numbered 35 ± 12/μL (n = 27, p < 0.001 vs. control) and patients who sustained NS (GDS > 1 at 1 month) had 75 ± 38/μL (n = 27; p < 0.001 vs. control and CO-recovered groups). Twice as many MPs carry IL-1β cargo as express surface-bearing IL-1β. The concentration is higher post-CO but does not correlate with NS. Those with NS have 43.8 ± 42.0 pg IL-1β /10⁶ MPs, and those with GDS = 1 have 33.0 ± 32.0 pg/10⁶ MPs, versus controls 5.4 ± 0.3 pg/10⁶ MPs, p < 0.001. In a murine CO model, MPs IL-1β cargo follows similar proportions to humans. Pharmacologic blockade of IL-1β using an IL-1 receptor antagonist or neutralizing anti-IL-1β antibody inhibited neuroinflammation and preserved neurological function. Results demonstrate that brain-derived MPs liberated via the glymphatic system to the peripheral circulation activate neutrophils which are the prime generators of IL-1β-bearing MPs that maintain a cycle of neuroinflammation. Targeting IL-1β disrupts MP-mediated inflammation. Full article

Severe pediatric asthma remains a significant clinical challenge despite advances in conventional therapy. Some children continue to experience persistent symptoms, recurrent exacerbations, and substantial morbidity despite optimized treatment with inhaled corticosteroids and long-acting bronchodilators. Advances in the understanding of asthma immunopathology, particularly type 2 (T2) inflammation, have led to the development of targeted biologics that modulate key inflammatory pathways. Several monoclonal antibodies are now approved for pediatric use, including the anti-immunoglobulin E (IgE) agent omalizumab, anti-interleukin (IL)-5 therapies such as mepolizumab, and the IL-4 receptor antagonist dupilumab. These biologics significantly reduce exacerbation rates, improve lung function, and decrease dependence on systemic corticosteroids in selected pediatric populations. Their effective use, however, requires careful assessment of clinical phenotypes and biomarkers, including blood eosinophils, serum IgE, and fractional exhaled nitric oxide. Uncertainties remain regarding treatment sequencing, duration, long-term safety, and cost-effectiveness. Agents targeting upstream epithelial cytokines, including tezepelumab, are broadening the therapeutic landscape. Despite this progress, pediatric evidence remains fragmented across age groups, biologic agents, study designs, and real-world cohorts, while many reviews focus on individual therapies or partly extrapolate from adult data. This review synthesizes pediatric evidence on efficacy, safety, biomarker-guided selection, age-related indications, and implementation challenges across approved and emerging biologics. It aims to provide clinicians with a practical framework for treatment selection and monitoring while identifying priorities for future pediatric research. Full article

Physical exercise is considered an effective and relatively safe practice to reduce or control levels of pro-inflammatory mediators during aging. However, findings are often interpreted primarily through statistical significance, while the magnitude and potential clinical relevance of observed effects receive less attention. Therefore, the primary objective of this cross-sectional study was to investigate whether regular physical exercise was associated with differences in circulating levels of systemic inflammatory mediators (high-sensitivity C-reactive protein [hsCRP], TNF-α, IL-6, IL-8, IL-10, and IL-12) among community-dwelling older adults, emphasizing the magnitude and potential clinical relevance of these differences rather than an interpretation based exclusively on statistical significance. The results suggest that exercisers exhibited hsCRP levels 0.68 mg/L lower than those observed among non-exercisers (95% CI: −0.98 to −0.34 mg/L; p = 0.001). Although serum IL-6 levels did not differ statistically between groups (p = 0.072), the interval estimates remained compatible with potentially relevant reductions among exercisers. The estimated between-group difference indicated that exercisers presented median IL-6 concentrations 4.34 pg/mL lower than non-exercisers (95% CI: −9.41 to 0.24 pg/mL). No meaningful differences were observed for TNF-α, IL-8, IL-10, or IL-12. Taken together, these findings suggest that regular physical exercise is associated with a more favorable inflammatory profile in older adults, particularly through lower hsCRP concentrations. The findings for IL-6 remain inconclusive but support the need for future studies with more precise estimates of the magnitude and potential clinical relevance of this association. Full article

Staphylococcus aureus (S. aureus), a primary exacerbating factor in eczema, remains a prevalent pathogenic public-health threat. The mechanism of mast cell/basophil degranulation in the context of S. aureus-exacerbated eczema remains unclear. We sought to investigate the direct effect of mast cell/basophil activation by S. aureus isolated from patients with severe eczema undergoing topical steroid withdrawal (TSW) and understand the mechanism of berberine (BBR) in inhibiting this activation. Clinical S. aureus strains (N = 8) were isolated from skin swabs of severe eczema patients and confirmed by sequencing. Human basophils (KU812), rat basophils (RBL-2H3) and murine mast cells (MC/9) were pre-treated with BBR for 48 h. and stimulated with heat-killed standard S. aureus- and clinical strains for 45 min, and degranulation was measured. BBR’s molecular-targets on basophils were identified by computational modeling and validated by qRT-PCR. BBR prevented degranulation following standard S. aureus stimulation in KU812, RBL-2H3 and MC/9 cells. BBR dose-dependently inhibited degranulation in KU812. BBR inhibited TNF-α and IL-4 release, and markedly suppressed the expression of FcεR1 (α, β, γ), TNFα, MAPK1, MAPK3, AKT2, CASP9, and CCND1 following standard S. aureus stimulation. BBR dose-dependently inhibited KU812 cell degranulation, markedly reduced TNF-α, IL-4, and MAPK1 and enhanced NFκB1A expression following clinical S. aureus strain stimulation. BBR inhibition of S. aureus-induced KU812 activation was at least associated with inhibition of MAPK-associated gene expression. This study provides novel insights into BBR’s effect in preventing S. aureus and human basophil interaction. Full article

Background/Objectives: Toxoplasma gondii is a globally distributed parasite responsible for significant morbidity in both humans and animals. VXN-Toxo, is an intranasal vaccine based on maltodextrin nanoparticles formulated with inactivated T. gondii parasites. A vaccination campaign conducted worldwide in zoological parks demonstrated high efficacy across multiple species and geographical regions. These findings suggest that VXN-Toxo may induce broad cross-reactive immunity against T. gondii strains circulating in various regions. Methods: To further characterize the immune mechanisms, we evaluated the cellular immune response induced by VXN-Toxo in C57BL/6 mice. Following vaccination, splenocytes were stimulated with antigens derived from multiple T. gondii strains, representing the major haplogroups (types I, II, III, and atypical strains). Results: ELISPOT analysis demonstrated that VXN-Toxo induced strong antigen-specific T cell responses, characterized by robust IFN-γ and IL-17 production upon stimulation with both homologous and heterologous antigens. Flow cytometry analysis further revealed the activation of both CD4⁺ and CD8⁺ T cells, with the notable presence of IFN-γ–producing CD8⁺ central and effector memory cells and CD4⁺ effector memory T cells. Conclusions: Altogether, these results indicate that VXN-Toxo induces a broad, T cell–mediated immune response with cross-reactive properties and highlight its potential as a promising vaccine candidate for both human and veterinary applications. Full article

Background/Objectives: Herpes simplex virus type 1 (HSV-1) is a global and prevalent pathogen, presenting significant clinical challenges because of its recurring infections, the development of drug resistance and severe clinical complications. This study evaluated the antiviral efficacy against HSV-1 of Acrocomia aculeata (A. aculeata) kernel oil, a Neotropical palm native to the Americas. Methods: The chemical profile of A. aculeata kernel oil was determined by gas chromatography with flame ionization detection (GC-FID). Antiviral activity was assessed using dose–response curves, time-of-addition assays, and quantification of intracellular viral genomes, viral gene transcripts, and IL-6 expression. A. aculeata kernel oil’s antiviral effect was also evaluated using an in vivo HSV-1 cutaneous infection model. Results: GC-FID analysis revealed lauric, oleic, and myristic acids as predominant components in the kernel oil. A. aculeata kernel oil exhibited potent antiviral activity against HSV-1. The oil inhibited HSV-1 early step post-entry, reducing the mRNA levels of the immediate-early genes ICP4 and ICP22, leading to the downregulation of early and late viral gene expression and intracellular viral genome. Furthermore, the oil suppressed IL-6 expression in infected cells. Importantly, A. aculeata kernel oil promoted the healing of cutaneous lesions in HSV-1-infected mice. Conclusions: These findings demonstrate that A. aculeata kernel oil is a promising candidate for developing novel antiviral and topical therapies against HSV-1. Full article

Current Parkinson’s disease (PD) therapies like Levodopa (L-DOPA) only provide symptomatic relief, highlighting the need for multi-target neuroprotective agents. This study investigates the mechanisms and preclinical effects of trans-vitisin B (tVB), an oligomeric stilbene, in PD models. In LPS-stimulated HMC3 and RAW 264.7 cells, tVB (0.1–10.0 µM) significantly suppressed reactive oxygen species (ROS), nitric oxide (NO), COX-2, and pro-inflammatory cytokines (IL-1β, TNF-α), while restoring HSP70 chaperone levels to normalize proteostasis. These findings were validated in vivo using C57BL/6 mice with rotenone-induced chronic PD. Administration of tVB attenuated motor deficits (Cylinder test) and reduced pathological freezing (Open Field) and working memory impairments (Y-maze) in this model, without inducing the dyskinesia-like side effects of L-DOPA treatment in rodents. Histologically, tVB mitigated the loss of dopaminergic neurons (TH⁺) in the substantia nigra, reduced microglial activation (IBA-1⁺) and neuronal NO synthase, and suppressed pathological phosphorylated Tau protein (p-TauSer202) accumulation. Unlike L-DOPA’s direct dopaminergic stimulation, tVB’s neuroprotective efficacy is mediated through multilevel regulation of key PD pathogenetic pathways, including neuroinflammation, oxidative stress, and impaired proteostasis. Full article

Cigarette smoke exposure is a major preventable risk factor for respiratory disease and drives oxidative and inflammatory lung injury, highlighting the urgent need for safe, multi-target interventions beyond conventional anti-inflammatory therapy. Formononetin (FMN), a naturally occurring isoflavone with antioxidant, anti-inflammatory, and microbiota-modulating potential, may offer a dietary-botanical strategy against smoke-related pulmonary damage. This study evaluated FMN against cigarette smoke extract (CSE)-induced lung injury and explored its associations with intestinal barrier integrity, gut microbiota, taurine metabolism, SLC6A6 expression, and NF-κB activation. In a CSE-challenged mouse model, oral FMN, particularly at 70 mg/kg, improved body weight gain, reduced the lung index, attenuated pulmonary histopathological injury, restored GSH/GSSG and SOD, decreased MDA, and suppressed TNF-α, IL-1β, and IL-6 expression. FMN also ameliorated colonic injury and restored ZO-1 and occludin expression. Exploratory 16S rRNA sequencing and fecal metabolomics indicated FMN-associated alterations in gut microbial composition and metabolic profiles, with taurine and hypotaurine metabolism identified as a candidate pathway for further investigation. FMN further restored lung taurine content and SLC6A6 expression while inhibiting NF-κB activation. These findings suggest that FMN alleviates CSE-induced lung injury and that this improvement is associated with coordinated changes in gut microbiota composition, taurine metabolism, SLC6A6 expression, and NF-κB activation. Full article

The dysregulation of immune homeostasis and the persistence of chronic, low-grade inflammation represent core pathophysiological drivers governing the onset and progression of metabolic and cardiovascular disorders. Myeloid-derived suppressor cells (MDSCs) comprise a highly heterogeneous population of immature myeloid cells that are rapidly mobilized from the bone marrow in response to biological stressors, such as sustained tissue injury and chronic inflammatory signaling. Historically evaluated within oncology and infectious disease frameworks, accumulating evidence highlights the pivotal, context-dependent roles of MDSCs in cardiometabolic environments. In conditions of obesity and type 2 diabetes (T2D), MDSCs undergo substantial expansion and accumulation within peripheral tissues, including adipose tissue and the liver. Functionally, MDSCs act as dynamic immunoregulators that can either buffer metabolic inflammation, via the secretion of interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and nitric oxide (NO) or, conversely, reflect and exacerbate disease progression depending on specific cellular subsets, glycemic control, and tissue localization. Within the vascular system, specific monocytic MDSC subsets demonstrate significant atheroprotective and cardioprotective capabilities by dampening Th1/Th17-mediated arterial wall inflammation, stabilizing atherosclerotic plaques, and preserving cardiac structural architecture during heart failure. However, phenotypic and functional heterogeneity poses a critical clinical challenge, as certain persistent or altered subsets correlate with heightened cardiovascular risk and adverse cerebrovascular outcomes. This review delivers a comprehensive synthesis of contemporary insights into MDSC biology at the intersection of obesity-associated diabetes and cardiovascular disease, characterizing their dualistic mechanisms, distinguishing preclinical causal mechanisms from human observational data. Moreover, we have established a comprehensive framework to reconcile the conflicting protective versus detrimental effects of MDSCs. And finally, we have also evaluated their potential clinical utility as candidate biomarkers, delineating the safety imperatives essential for translating MDSC-targeted therapeutic interventions into clinical practice. Full article

Background: Hyperlipidemic acute pancreatitis (HAP) is a severe disease driven by systemic lipid overload. While free fatty acids (FFAs) are known to mediate pancreatic lipotoxicity, the intracellular enzymatic mechanisms generating these toxic lipid mediators remain unclear. We aimed to identify the core metabolic drivers linking systemic hyperlipidemia to local pancreatic injury and evaluate targeted prophylactic strategies for HAP. Methods: We integrated public transcriptomic datasets of severe AP and obesity/hyperlipidemia. Three machine learning algorithms were employed to identify comorbidity-associated signature genes. The underlying mechanisms were explored via gene set variation analysis, immune infiltration profiling, and single-cell in silico knockout. In vivo validation was performed using a P-407/caerulein-induced HAP mouse model treated with WWL113, followed by comprehensive histological, biochemical, and lipidomic analyses. Results: A robust three-gene signature (FASN, CES1, IL10) was identified with excellent diagnostic accuracy. Notably, within this signature, the triglyceride hydrolase CES1 was aberrantly upregulated, serving as the primary driver of a maladaptive lipolytic shift. CES1 overexpression was strongly correlated with neutrophil infiltration. Single-cell virtual knockout suggested a potential association between Ces1d and markers of endothelial barrier disruption and neutrophil chemotaxis. In vivo, WWL113 significantly attenuated HAP-induced pancreatic necrosis and systemic inflammation. Crucially, lipidomics confirmed that WWL113 sequestered exogenous lipids in inert triglyceride states, drastically reducing toxic FFAs. Conclusions: This study highlights CES1 as a critical intracellular mediator of lipotoxicity in HAP. Pharmacological inhibition of CES1 effectively halts maladaptive lipolysis, providing proof-of-mechanism for a metabolism-directed prophylactic strategy for HAP. Full article

Propolis is a resinous natural product collected by bees from plant sources to protect the hive. Its chemical composition varies according to bee species and environmental conditions, resulting in differences in its biological activities. This study aimed to evaluate the biological properties of stingless bee propolis collected from different provinces in Thailand, with particular attention to two native species, Tetragonula pegdeni and Tetragonula laeviceps. These two species of Tetragonula are commonly found in tropical regions of the country. The investigation focused on their antioxidant, antimicrobial, and anti-inflammatory activities. The propolis extract from T. laeviceps stingless bee (sample D) exhibited the highest total phenolic and flavonoid contents, at 29.59 mg GAE/g extract and 73.95 mg QUE/g extract, respectively. Among the propolis extracts, T. pegdeni stingless bee propolis extract (sample A) showed the greatest antioxidant activity of 7.08 ± 0.18 GAE/g extract and 75.64 ± 3.07 mg TEAC/g extract by the DPPH and ABTS assays, respectively, together with the highest FRAP value of 48.54 ± 0.48 mg FeSO₄/g extract. The antibacterial efficacy of these extracts was further evaluated against skin pathogenic bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Micrococcus luteus, and Cutibacterium acnes. Inhibition zones ranged from 7.00 to 14.00 mm when determined by the agar disc diffusion method. Moreover, antibacterial activity was investigated by broth dilution assay, and MIC and MBC values ranged from 0.97 to 125 mg/mL. The cytotoxicity test of propolis extracts using RAW264.7 macrophage cells showed cell viability above 70%, and the selected concentrations were used for further anti-inflammatory evaluation. T. pegdeni stingless bee propolis extracts (samples A and B) demonstrated anti-inflammatory activity by reducing NO production and decreasing the expression of iNOS, COX-2, and IL-1β genes in LPS-stimulated RAW264.7 macrophage cells. LC–MS analysis revealed differences in chemical profiles among the propolis extracts and various bioactive compounds, including phenolic acids, flavonoids, xanthones, terpenoids, triterpenoids, and curcuminoids were identified. Therefore, Thai stingless bee propolis demonstrated potential as a natural source of bioactive compounds with antioxidant, antibacterial, and anti-inflammatory properties. Full article