Search Results (10,951)

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is significantly contributed to by epigenetics. We developed a machine learning-based framework to identify DNA methylation biomarkers associated with AD classification and severity. Genome-wide methylation data from peripheral blood were processed using four feature selection algorithms: coarse approximation linear function (CALF), elastic net (EN), minimum redundancy maximum relevance (mRMR), and recursive feature elimination with cross-validation (RFECV). The integrative framework identified a central panel of 8 CpG sites that achieved an area under the curve (AUC) of 1.00 in the test set. This panel demonstrated high disease specificity, showing poor classification performance for systemic lupus erythematosus (AUC = 0.46), Crohn’s disease (AUC = 0.50), and oral squamous cell carcinoma (AUC = 0.58). Severity prediction using RFECV-selected 63 CpG sites (RFE63) achieved high accuracy across classifiers, with Random Forest (accuracy = 0.94) outperforming the others. The functional enrichment of CpG-associated genes highlighted key immune-related transcriptional regulators, including STAT5A, RUNX1, MEIS1, and PAX4. These genes are linked to chromatin remodeling, T helper cell differentiation, and interleukin-2 regulation, which are critical in AD pathogenesis and severity. Our findings demonstrate the utility of machine learning-integrated epigenomics in identifying robust, disease-specific biomarkers for AD diagnosis and monitoring, offering new insights into the molecular mechanisms underlying childhood AD. However, further validation in large-scale independent cohorts is required to confirm their clinical robustness and generalizability. Full article

Background: Obesity is associated with alterations in the immune response through increased systemic inflammation. This systemic inflammatory state may increase the risk of peri-implantitis, a condition characterized by infection and tissue destruction around dental implants. Therefore, this cross-sectional clinical study aimed to investigate the association between obesity and peri-implant health. Methods: In this observational clinical study, a total of 80 patients were evaluated, including a peri-implant healthy non-obese control group (CG) (n = 20), peri-implantitis non-obese group (PG) (n = 20), peri-implant healthy obese group (OG) (n = 20), and peri-implantitis obese group (POG) (n = 20). Peri-implant clinical measurements (plaque index [PI], gingival index [GI], bleeding on probing [BOP], and probing depth [PD]) were obtained from the participants. In addition, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and matrix metalloproteinase-8 (MMP-8) levels were measured in peri-implant crevicular fluid (PICF) samples. Results: PI, GI, BOP, and PD levels were significantly higher in the POG and PG than in the other groups (p < 0.05). PICF volume was found to be higher in the POG and PG than in the control group (p < 0.05). TNF-α levels increased significantly in all groups compared with the control group, and IL-1β levels were highest in the POG (p < 0.05). Conclusions: The findings of this cross-sectional study suggest a potential association between increased proinflammatory cytokine levels and altered peri-implant inflammatory responses in patients with obesity. Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT07183163) on 18 September 2025 (retrospectively). Full article

The efficient delivery of small interfering RNAs (siRNAs) to immune and respiratory cells represents a key methodological challenge in developing inhaled RNA interference (RNAi) approaches. A central question is whether siRNA functionality is preserved following aerosolization, as the mechanical stress of nebulization may compromise siRNA integrity and silencing activity. Here, we report a proof-of-concept study using THP-1-derived macrophage-like cells as a tractable in vitro model to characterize jet nebulization for siRNA delivery. Three siRNA candidates targeting interleukin-1 beta (IL-1β) were computationally designed and validated for potent silencing activity and low cytotoxicity. Using a commercially available, off-the-shelf jet nebulizer combined with Lipofectamine RNAiMAX, we demonstrate that siRNA-lipoplexes retain their gene-silencing activity after aerosolization, achieving robust IL-1β knockdown. The delivery efficiency was influenced by siRNA-lipoplex complexation, highlighting the importance of formulation parameters. These findings establish a practical and accessible in vitro platform for evaluating nebulized siRNA functionality, providing a foundation for future studies in more complex and physiologically relevant airway models. Full article

Obesity represents a heterogeneous metabolic disorder characterized by substantial interindividual variation in inflammatory status, insulin sensitivity, and cardiometabolic risk. Traditional anthropometric measures fail to capture this metabolic diversity, limiting risk stratification and personalized intervention strategies. This review critically examines nutritional and metabolic biomarkers that reflect the physiological dysregulation underlying obesity, including adipokines (leptin, adiponectin, resistin), inflammatory markers (C-reactive protein, interleukin-6, TNF-α), insulin resistance indices (HOMA-IR, fasting insulin, HbA1c), and lipid metabolism indicators (LDL cholesterol, triglycerides, HDL cholesterol, and liver enzymes such as ALT and GGT). Among these, elevated CRP, reduced adiponectin, and increased HOMA-IR have demonstrated the strongest clinical utility for early metabolic risk identification. We further evaluate emerging biomarkers—including circulating microRNAs, gut microbiota-derived metabolites (short-chain fatty acids, TMAO, lipopolysaccharides), and bile acid profiles—which offer additional mechanistic insight into diet–microbiome–host interactions. We systematically assess the mechanistic basis, clinical relevance, and nutritional modulation of each biomarker class, emphasizing how dietary composition—particularly fatty acid quality, fiber intake, and overall dietary patterns such as the Mediterranean diet—influences biomarker profiles and metabolic outcomes. Furthermore, we explore how biomarker-based phenotyping enables precision nutrition approaches by identifying individuals most likely to benefit from specific dietary interventions. Integration of multi-biomarker panels with clinical and genetic data holds promise for advancing from population-based dietary guidelines toward individualized nutrition strategies that optimize metabolic health and prevent obesity-related complications. Future research should prioritize validating biomarker-guided intervention frameworks, establishing standardized thresholds across diverse populations, and developing clinically implementable tools for personalized nutritional medicine. Full article

Dental amalgam remains widely used in restorative dentistry due to its durability and cost-effectiveness, yet concerns persist regarding potential biological effects related to mercury release. This narrative review critically synthesizes current evidence on oral mucosal alterations and salivary biomarker changes reported in association with amalgam restorations. Experimental research supports biological plausibility for oxidative and inflammatory responses to mercury exposure; however, most human evidence derives from observational studies demonstrating heterogeneous associations rather than consistent causal relationships. Reported variations in salivary biomarkers, including interleukin-8 and ceruloplasmin, are generally modest and influenced by confounding factors such as periodontal status, smoking, and systemic inflammation. Histopathological findings adjacent to amalgam restorations include epithelial and inflammatory changes, though many are nonspecific and comparable to other chronic irritative conditions. Overall, current clinical and epidemiological data do not indicate uniform or clinically significant adverse effects in the general population attributable solely to dental amalgam. Regulatory phase-down initiatives primarily reflect environmental and precautionary policies. Available evidence supports a balanced and evidence-based interpretation of amalgam-related biological findings in contemporary dental practice. Full article

Studies have shown that IL-10 has therapeutic potential for inflammatory diseases. However, it is challenging to use IL-10 as a therapeutic drug because it also possesses pro-inflammatory functions. To reduce these pro-inflammatory effects of IL-10, we have designed three IL-10 mutants using structure-based computational design technology. We demonstrated that these mutants exhibited significantly lower activity in IL-10-responsive cell lines than wild-type IL-10. Using recombinant adeno-associated virus (rAAV8) vectors expressing wild-type or mutant IL-10 molecules, we performed gene therapy experiments in IL-10 KO mice. The results showed that our vectors mediated high levels of transgene expression. Importantly, IL-10 gene therapy increased body weight gain, reduced colon injury, and prevented the development of inflammatory bowel disease (IBD). Moreover, IL-10 mutant gene therapy elicited significantly lower stimulation of CD8 T and NK cells compared with the wild-type IL-10 group. In summary, our IL-10 mutants provide a protective effect comparable to wild-type IL-10 in the IL-10 KO mouse model, suggesting that they may potentially have reduced pro-inflammatory function. While rigorous investigations of safety and efficacy in different disease models will be required, these results indicate the therapeutic potential of IL-10 mutant gene therapy for inflammatory diseases such as IBD. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid-beta (Aβ) accumulation, oxidative stress (OS), and chronic inflammation drive synaptic dysfunction and cognitive decline. Molecular hydrogen (H₂) has emerged as a candidate neuroprotective gas with selective antioxidant and anti-inflammatory properties, although its efficacy in amyloid-driven pathology remains incompletely defined. In this study, 5xFAD transgenic mice harboring human amyloid precursor protein (APP) and presenilin-1 (PSEN1) mutations and age-matched C57BL/6 wild-type mice were exposed to 2% H₂ by inhalation for 1 h/day over 4 weeks. H₂ inhalation reduced hippocampal reactive oxygen species (ROS), increased systemic catalase activity, and enhanced hippocampal ATP levels. In serum, H₂ decreased tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, restored IL-10, and partially normalized IL-13, shifting the peripheral environment toward a less pro-inflammatory profile. In the hippocampus, H₂ upregulated nuclear factor erythroid 2-related factor 2 (NRF2), attenuated nuclear factor kappa B (NF-κB) activation, reduced the BAX/BCL-2 ratio, preserved neuronal nuclei (NEUN) expression, and decreased hippocampal Aβ42 burden. Collectively, these findings indicate that H₂ inhalation confers multi-faceted neuroprotection in 5xFAD mice by restoring redox homeostasis, suppressing inflammation, improving mitochondrial function, and limiting Aβ accumulation. Full article

In this study, we examine the effectiveness of combining interleukin-2 (IL-2) with highly active antiretroviral therapy (HAART) in controlling HIV replication. A mathematical model of the immune system is developed to analyze immune recovery when IL-2 is administered alongside HAART. We investigate the stability of the endemic equilibrium and Hopf bifurcation and determine the direction and stability of periodic solutions using center manifold theory. Numerical simulations are conducted to support the theoretical findings. The results show that the disease-free equilibrium is stable when the basic reproduction number $R_0<1$, while the endemic equilibrium exists when $R_0>1$. Our results also reveal the presence of a subcritical Hopf bifurcation in the system. An optimal control problem is also studied, showing that the combined therapy of IL-2 and HAART improves treatment outcomes, reduces side effects, and has a unique optimal control pair. Sensitivity analysis further highlights the importance of system parameters in influencing treatment effectiveness. Full article

Myeloid differentiation factor 88 (MyD88) signaling plays a central role in inflammatory pathway activation. Adipose-derived interleukin-10 (IL-10), which is induced by insulin and lipopolysaccharides, suppresses hepatic glucose production. This study investigated the role of MyD88/IL-10 signaling in diabetes-induced systemic inflammation and hepatic gluconeogenesis. Stromal vascular fractions (SVFs) were isolated from the adipose tissue of Lepr^db/db and Lepr^db/dbMyD88^−/− mice and treated with IL-10 followed by analysis of inflammatory cytokine expression. IL-10 (10 or 50 ng) was injected into adipose tissue of type 2 DM (T2DM) (Lepr^db/db) mice to investigate its effect on blood dipeptidyl peptidase-4 (DPP4) activity, insulin resistance, and hepatic gluconeogenic signaling. Hepatic inflammatory markers, gluconeogenic gene expression, and metabolic parameters were assessed. Compared with wild-type mice, Lepr^db/db mice exhibited significantly reduced FOXP3 protein expression and IL-10 levels in adipose tissue, accompanied by increased blood DPP4 activity and adiponectin levels, elevated hepatic inflammatory cytokines, and increased G6pc and Pck1 mRNA expression. In contrast, Lepr^db/dbMyD88^−/− mice showed increased Foxp3 protein and PDGFα mRNA expression, decreased IL-6 and CCL2 mRNA expression in SVFs, increased IL-10 levels in adipose tissue, and lower blood adiponectin and ALT levels. MyD88 deletion also attenuated Kupffer cell accumulation, hepatic inflammatory cytokine expression, and gluconeogenic gene expression. In vitro, IL-10 treatment of SVFs from Lepr^db/db mice significantly reduced IL-6 and CCL2 expression and increased Foxp3 mRNA expression. In vivo, adipose IL-10 injection increased Foxp3 and IL-10 expression, expanded Treg cells in SVFs, and activated hepatic Akt signaling, while suppressing pJNK and pNF-κB signaling. These changes were accompanied by reduced blood DPP4 activity, ALT and adiponectin levels, decreased Kupffer cell-derived inflammatory cytokines, reduced hepatic G6pc and Pck1 expression, and improved glucose tolerance. MyD88 signaling induces adipose IL-6 and CCL2, liver inflammation and gluconeogenesis, and blood DPP4 activity by reducing IL-10 and Foxp3 of adipose tissue in T2DM. Enhancing adipose IL-10 induces Treg expansion, inhibits JNK and NF-κB signaling, and alleviates hepatic gluconeogenesis and insulin resistance. MyD88 inhibition or IL-10 elevation in adipose tissue may represent a novel strategy for metabolic syndrome. Full article

Background: The integration of anti-disialoganglioside GD2 (anti-GD2) immunotherapy during induction chemotherapy has emerged as a promising strategy to improve outcomes in high-risk neuroblastoma (HR-NB). This study evaluated the end-of-induction (EOI) response and tolerability of a modified N7 induction regimen combined with dinutuximab beta in a Hong Kong paediatric cohort. Methods: A retrospective territory-wide analysis was conducted on nine HR-NB patients treated from 2022 to 2025. They received a modified N7 chemotherapy backbone with dinutuximab beta (17.5 mg/m²/day for 4 days per cycle), alongside granulocyte–macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin-2. Response was assessed using the Revised International Neuroblastoma Response Criteria (INRC), and toxicity was graded according to the Common Terminology Criteria for adverse events (CTCAE). Results: The EOI objective response rate was 78% (7/9 patients) for the primary tumour site and 100% at metastatic sites. No patient exhibited progressive disease. A modified Curie score of ≤2 on MIBG scan was achieved in 78% of patients. Grade 3 or higher toxicities, including neutropenic fever, enterocolitis, and capillary leak syndrome, were observed in eight patients but were manageable. Conclusions: The incorporation of dinutuximab beta into a modified N7 induction regimen demonstrates a satisfactory EOI response rate and a manageable safety profile in children with HR-NB. These preliminary results support the feasibility of this chemoimmunotherapy approach and warrant further investigation in larger cohorts to confirm its efficacy in long-term survival outcomes. Full article

People living with HIV (PLWH) receiving effective antiretroviral therapy (ART) continue to exhibit chronic immune activation and systemic inflammation despite virological suppression. The viral envelope glycoprotein gp120, which binds the CD4 receptor and mediates viral entry, has been implicated in pro-inflammatory and pro-apoptotic effects in neuronal and endothelial cells. Although gp120 is expressed on the viral surface, its oligomeric structure and its ability to form immune complexes with circulating antibodies may reduce the sensitivity of standard detection assays in serum. Soluble gp120 has been associated with increased levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as chemokines. These mediators may contribute to blood–brain barrier dysfunction, endothelial injury, vascular smooth muscle alterations, and subsequent neurodegenerative and cardiovascular complications. Importantly, gp120 shedding may persist due to viral reservoirs and intermittent reactivation, even during ART. Fostemsavir inhibits the interaction between gp120 and CD4, preventing viral entry and potentially limiting gp120-mediated pathogenic effects. Beyond antiviral activity, this mechanism suggests a potential role in attenuating gp120-mediated inflammation. This review discusses the biological effects of gp120 and the rationale for targeting it therapeutically in PLWH. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease driven by immune dysregulation and epidermal barrier dysfunction. Current therapeutic options are often limited by safety concerns or suboptimal tolerability. In this study, we isolated and structurally characterized GRB-H—a λ-carrageenan-enriched sulfated hybrid galactan from the marine red alga Gigartina radula—as a complex polysaccharide containing κ-, ι-, μ-, ν-, and λ-carrageenan structural units, and systematically evaluated its anti-AD potential using both in vitro and in vivo models. In vitro, GRB-H significantly suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in RAW 264.7 macrophages, and reduced 2,4-dinitrochlorobenzene (DNCB)-evoked TNF-α and IL-1β expression in HaCaT keratinocytes. In a DNCB-induced murine model of AD, topical application of GRB-H markedly ameliorated skin inflammation, epidermal hyperplasia, and dermal immune cell infiltration. GRB-H treatment lowered total serum immunoglobulin E (IgE) levels, restored the imbalanced Th1/Th2 cell ratio in the spleen, and downregulated the mRNA expression of key inflammatory cytokines—including TNF-α, IL-4, IL-5, IL-31, and interferon-γ (IFN-γ)—in lesional skin. Collectively, these findings demonstrate that GRB-H alleviates AD symptoms through coordinated local anti-inflammatory and systemic immunomodulatory actions, highlighting its promise as a marine-derived candidate for the topical management of AD. Full article

Background: Systemic inflammation is a key driver of heart failure (HF) progression across all ejection fraction (EF) phenotypes, with diet emerging as a modifiable factor influencing cardiac metabolism and inflammatory signaling. This narrative review integrates current evidence on the inflammatory mechanisms underlying HF, their links with common comorbidities and emerging anti-inflammatory therapeutic strategies, with a particular focus on the role of nutrition in supporting healthy cardiac metabolism. Methods: We searched MEDLINE/PubMed, EMBASE, Web of Science, the Cochrane Library, Scopus and reference lists of relevant publications using terms related to systemic inflammation, dietary patterns and HF prioritizing high-impact studies on nutrition–inflammation–HF interactions published from 2000 onward. Results: Major HF comorbidities sustain chronic, low-grade inflammation through elevated cytokine activity. Dietary patterns—especially those with high Dietary Inflammatory Index (DII)—substantially shape inflammatory milieu. The Mediterranean diet appears to have a favorable inflammatory profile with reduction in circulating pro-inflammatory biomarkers, especially C-reactive protein (CRP) and interleukin-6 (IL-6). Established therapies for HF with reduced ejection fraction and vagus nerve stimulation elicit anti-inflammatory efficacy through cytokine suppression. Sodium glucose cotransporter-2 (SGLT2) inhibitors demonstrate positive metabolic effects and anti-inflammatory actions through decrease in IL-6 and tumor necrosis factor-α (TNF-α). Interleukin-1 blockade has produced heterogeneous clinical outcomes, while definitive findings examining the role of IL-6 inhibitors in inflammation suppression and possible benefit on cardiac outcomes are anticipated. Preliminary data show the potential synergistic effects of dietary patterns/nutrients and pharmacological agents combination on improvement of endothelial function and attenuation of the fibrotic process, although there is a need for further research in large-scale trials. Conclusions: Systemic inflammation demonstrates a key role in HF initiation and progression, and the effect of diet on inflammatory pathways is central. Dietary patterns targeting inflammation-related mechanisms (inflammasome, gut dysbiosis) can lead to attenuation of systemic inflammatory response and restoration of cardiac metabolic flexibility. A deeper mechanistic discernment of cardiac inflammatory cascades, together with identification of HF subpopulations with excessive inflammatory activity, may facilitate the design of targeted randomized controlled trials (RCTs) aiming for novel personalized, inflammation-targeted HF therapies with potential clinical benefit. Full article

Background/Objectives: Multiple Sclerosis (MS) is a chronic immune-mediated disorder characterized by neuroinflammation and neurodegeneration. Increasing evidence implies the kynurenine pathway (KP) in the MS pathophysiology; however, data from Mexican populations are lacking. This exploratory study aimed to characterize central and circulating KP metabolites in Mexican patients with MS and to investigate potential genetic variants in KP-related genes. Methods: Serum concentrations of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), as well as cerebrospinal fluid (CSF) levels of KYNA, quinolinic acid (QUIN), interleukin-4 (IL-4), and interleukin-6 (IL-6), were determined in treatment-naïve relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and treated PMS patients. Serum levels were compared with those of healthy controls, and CSF findings contrasted with those of non-MS neurological patients and individuals with neurocysticercosis (NCC). Public whole-exome datasets were analyzed for variants in KP-related genes, and target exome sequencing was performed in three Mexican patients with MS. Results: Serum concentrations of KYNA and 3-HK were decreased in MS patients compared with healthy controls. CSF KYNA and QUIN levels did not differ significantly among MS subtypes or the non-MS neurological group, but they were lower than those observed in NCC. IL-4 and IL-6 were detectable in MS CSF samples, supporting the presence of intrathecal inflammation. Genetic and bioinformatic analyses identified variants in genes encoding KP enzymes in both public MS datasets and in Mexican patients with MS. Conclusions: These findings indicate an altered KP metabolism in Mexican MS patients, particularly during the relapse phase, and suggest a possible contribution of genetic variability. Further large-scale studies are needed to confirm these observations and to determine the functional implications of KP-related genetic variants in MS. Full article

Background: Circulating cytokines and their soluble receptors in body fluids have been implicated in the pathogenesis of multiple sclerosis (MS). Alterations in serum levels of pro- and anti-inflammatory cytokines and/or their soluble receptors can dysregulate central nervous system (CNS) signaling pathways and, therefore, may serve as potential biomarkers for the diagnosis of MS. Therefore, the primary end-point of this study is to investigate the utility of various cytokines and their soluble receptors as diagnostic biomarkers in MS. The secondary outcome is also to assess whether these cytokines are useful in differentiating the severity of MS. Methods: In this case–control study, we compared a panel of pro-inflammatory interleukins (ILs), including IL18 and tumor necrosis factor-alpha (TNFα), soluble IL receptors (sIL7Rα and sIL2Rα), and insulin-like growth factor-1 (IGF-1) in 45 MS patients and in 45 healthy control individuals matched for sex and age. Associations of these biomarkers with age, disease severity (Expanded Disability Status Scale [EDSS]), disease duration, and age at first MS symptom onset were also assessed. Results: Serum levels of cytokines and soluble IL receptors were elevated in MS patients compared to healthy controls. IGF-1 was lower (p < 0.001) in the MS patients than in the healthy individuals. The serum level of IGF-1 was higher (p < 0.01) in the remitting-relapsing phase compared to the primary progression and secondary progression stages. Similarly, only IGF-1 was more elevated (p < 0.01) in the mild stage compared to the moderate stage based on the EDSS score. Receiver operating characteristic (ROC) curve analysis demonstrated that IL18 had excellent discriminatory power for the diagnosis of MS (p < 0.001), with an area under the curve (AUC) of 0.96 ± 0.017, followed by IGF-1 (p < 0.001), which showed strong diagnostic performance (AUC = 0.873 ± 0.037). Soluble (s) IL2Rα exhibited fair diagnostic accuracy (p < 0.001; AUC = 0.717 ± 0.054). In contrast, sIL7Rα and TNFα showed poor discriminatory power despite statistical significance (p < 0.01), with AUC values of 0.675 ± 0.057 and 0.687 ± 0.056, respectively. Results of regression analysis revealed that EDSS, duration of disease, and use of any treatment had no impact on the cytokines. Similarly, no significant correlations were noted between these confounders and cytokines, except a moderate negative correlation (−0.418) between IGF-1 and EDSS. Conclusions: IL18 and IGF-1 have the potential to be used as biomarkers in distinguishing MS from healthy individuals. However, both biomarkers failed to demonstrate the discrimination between various phenotypic patterns of disease, limiting their utility for disease stratification. Future studies with larger, longitudinal cohorts and multi-marker panels are warranted to validate these results and to explore whether combining cytokines with imaging or genetic markers can improve prognostic precision. Full article