Search Results (628)

Major depressive disorder (MDD) is a prevalent psychiatric disorder in which epigenetic mechanisms, particularly DNA methylation (DNAm), may contribute to disease vulnerability and treatment response. Epigenome-wide association studies (EWAS) have increasingly investigated longitudinal methylomic changes associated with therapeutic interventions in depression; however, methodological heterogeneity limits comparability across studies. This critical review examined the methodologies and findings of longitudinal EWAS evaluating DNAm changes related to treatment response in MDD and treatment-resistant depression (TRD). A literature search identified seven studies published up to 20 June 2026. Six studies investigated non-pharmacological interventions, including electroconvulsive therapy, trauma-focused psychotherapy, and cognitive interventions, and one study explored pharmacotherapy. Considerable heterogeneity was observed regarding sample size, biospecimen type, methylation platforms, preprocessing pipelines, covariate adjustment, statistical modeling, and longitudinal sampling schedules. Most studies used Illumina EPIC array-based workflows and mixed-model analytical approaches, while one study employed sequencing-based methylation profiling. Overall, treatment-related methylation changes were modest and often limited to specific CpG sites or differentially methylated regions associated with immune, inflammatory, stress-related, and neurobiological pathways. Current evidence supports the feasibility of longitudinal EWAS approaches in depression research but highlights the need for larger cohorts, methodological standardization, and integration with multi-omics and clinical data to improve reproducibility and biomarker discovery. Full article

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity. Full article

Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody–drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy. Full article

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease with substantial impact on quality of life. The introduction of biologics and Janus kinase (JAK) inhibitors has markedly transformed systemic treatment strategies. However, long-term prospective real-world registries evaluating drug survival, safety, phenotype-specific treatment response, and post-discontinuation outcomes remain limited, particularly in Asian populations. Methods: The Western Japan Atopic Dermatitis Registry (WJADR) is a multicenter, prospective, observational registry coordinated by Kyushu University and collaborating institutions across western Japan. Patients initiating or currently receiving systemic therapy for AD are enrolled. Longitudinal data collection includes clinical phenotype classification, disease course classification, treatment exposure, physician-assessed severity scores, patient-reported outcomes, biomarkers, and safety information. The primary outcome is drug survival, while secondary outcomes include clinical improvement, adverse events, phenotype–treatment interactions, biomarker–treatment correlations, and treatment-switch patterns. Results: WJADR was designed as a phenotype-integrated real-world registry to evaluate comprehensive systemic treatment strategies and post-discontinuation outcomes in AD prior to the completion of patient enrollment and outcome analyses. Unlike existing registries primarily focused on biologic initiator cohorts or treatment burden, WJADR integrates clinical phenotypes, biomarkers, and longitudinal outcomes to support precision medicine approaches. Conclusions: WJADR represents the first large-scale multicenter prospective AD registry in western Japan and may provide ethnicity-specific real-world evidence to support long-term safety evaluation, treatment optimization, and phenotype-guided therapeutic strategies in AD. Full article

Background/Objectives: Parkinson’s disease (PD) exhibits marked sexual dimorphism, with a higher incidence and earlier onset in men than in women. However, the impact of biological sex on systemic molecular alterations in PD remains poorly understood. This pilot study aimed to identify sex-specific circulating signatures associated with PD. Methods: Serum samples from a selected cohort of PD patients and healthy controls (HC) of both sexes were analyzed using an integrated biochemical and ¹H NMR-based metabolomic approach. Oxidative stress markers, antioxidant proteins, inflammatory mediators, matrix metalloproteinases, α-synuclein species, and circulating antibodies were evaluated. Results: This analysis indicated that, while global oxidative stress markers were unchanged, sex-related differences in antioxidant pathways were observed as suggested by the reduced Nrf2 expression observed in PD females and increased IL-6 levels, above all in male PD patients. MMP3 levels were significantly higher in female PD patients compared with males. Male patients showed higher levels of 52 kDa protease-resistant α-synuclein species, while females exhibited increased antibody titers against both monomeric and aggregated forms. Metabolomic profiling suggested a disease-associated metabolic remodeling in PD, with distinct sex-related metabolic signatures and a more pronounced and widespread metabolic dysregulation in males. Conclusions: These findings suggest that biological sex may contribute to systemic molecular heterogeneity in PD, with trends indicating more pronounced inflammatory and metabolic alterations in males and distinct immune-related responses in females. Given the exploratory nature of the study and the limited sample size, these observations should be interpreted cautiously and require validation in larger, independent cohorts. Nevertheless, the results support the importance of considering sex-related molecular differences in future biomarker studies and precision medicine approaches for PD. Full article

Stroke remains one of the leading causes of death and disability worldwide, yet its clinical management is constrained by substantial biological heterogeneity that single-biomarker and single-omics approaches fail to resolve. The integration of multiple molecular data layers, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and immunomics, offers a transformative framework for investigating the underlying neuroinflammatory mechanisms of different stroke subtypes and endotypes. In this review, we synthesize the current multi-omics evidence in stroke by examining how genetic variants propagate through regulatory and immune pathways and generate measurable molecular signatures and clinically relevant biomarkers. We investigate the roles of microglia, infiltrating monocyte-derived macrophages, astrocytes, neutrophils, T cells, and endothelial cells as interacting nodes in the neuroimmune network after stroke, and analyze how spatially resolved single-cell transcriptomics illuminate state-specific programs previously undetectable in bulk tissue analyses. We discuss how proteomics and metabolomics translate these cellular programs into actionable circulating biomarkers and examine emerging evidence on blood–brain barrier disruption and neurovascular unit remodeling as multi-omics-defined targets. We then explore AI and machine learning frameworks enabling the integration of heterogeneous, high-dimensional datasets for endotype classification, patient stratification, and therapeutic response prediction. Finally, we address translational barriers, including analytical standardization, multi-ancestry generalizability, and regulatory readiness, and propose a roadmap for precision stroke medicine based on systems immunology. The core conceptual point of this review is the shift from describing omics findings in stroke cases to redefining biologically meaningful neuroinflammatory endotypes and using multi-omics to enable precision cerebrovascular medicine. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and fibrosis involving the skin and internal organs. Interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cardiac involvement remain major causes of morbidity and mortality, yet prediction of disease progression and therapeutic responsiveness remains difficult. Methods: This narrative review summarizes studies of circulating blood biomarkers in SSc, with emphasis on literature published since 2020 and on Japanese multicenter longitudinal cohort studies. Disease-specific autoantibodies were intentionally excluded from the main scope, and the review focuses on soluble biomarkers measurable in peripheral blood that reflect inflammation, endothelial injury, and fibrotic remodeling. Results: Multiple cytokines, chemokines, adhesion molecules, endothelial markers, extracellular vesicle-associated molecules, and extracellular matrix (ECM)-related molecules have been associated with disease activity, organ involvement, prognosis, and therapeutic response in SSc. Clinically established biomarkers such as KL-6 and surfactant protein-D (SP-D) for SSc-associated interstitial lung disease (ILD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for pulmonary arterial hypertension (PAH), are already used as adjunctive tools in routine clinical assessment, whereas many other candidate biomarkers, including interleukin (IL)-6, CCL2, CXCL8, CXCL4, intercellular adhesion molecule-1 (ICAM-1), CCL18, periostin, endostatin, endothelin-1, extracellular vesicle signatures, and ECM turnover markers remain at varying stages of clinical validation. In particular, Japanese multicenter longitudinal studies have demonstrated the prognostic significance of circulating chemokines and adhesion molecules in early SSc and, more recently, identified biomarker-based clusters associated with distinct pulmonary trajectories. Recent multidimensional proteomic and transcriptomic approaches further support biologically based patient stratification in SSc. Conclusions: Blood biomarkers may contribute to risk stratification, prediction of organ progression, and future precision medicine in SSc. Integrated biomarker signatures may better capture the biological heterogeneity of SSc than single biomarkers alone. However, most candidate biomarkers still require external validation, assay standardization, and demonstration of incremental value over conventional clinical variables before routine clinical implementation. Full article

Ischaemic stroke induces a dynamic neuroimmune response in which microglia act as central regulators of both secondary injury and tissue repair. In the acute phase, microglial activation amplifies neuronal damage through inflammatory signalling and vascular dysfunction; over subsequent days, these cells undergo coordinated transcriptional and metabolic reprogramming toward reparative states. The repeated failure of immunomodulatory therapies in clinical translation, however, suggests that current approaches fundamentally mischaracterise the underlying biology. We propose that microglial state transitions are governed not by discrete linear pathways but by a coupled regulatory network integrating proteostatic clearance, receptor-mediated signalling, inflammasome activation, and intracellular metabolism. Within this network, impaired clearance of cellular debris sustains exposure to damage-associated molecular patterns, perpetuating inflammasome activity and a pro-inflammatory metabolic programme; conversely, restoration of clearance capacity shifts network equilibrium toward resolution and repair. Microglial phenotypes therefore emerge from dynamic shifts in network state rather than progression through fixed activation stages. This framework accounts for the limited efficacy of non-selective or temporally misaligned interventions and identifies the post-acute transitional phase as a window of maximal network plasticity. Aligning therapy with the temporal and functional dynamics of this network—guided by phase-specific biomarkers—provides a mechanistic basis for precision immunomodulation and improved clinical translation in ischaemic stroke. Full article

Metabolic syndrome (MeS) is a major risk factor for cardiovascular disease and is characterized by chronic low-grade inflammation, immune dysregulation, and metabolic abnormalities. However, the molecular mechanisms linking MeS to diabetic coronary artery disease (DMCAD) remain incompletely understood. Publicly available peripheral blood mononuclear cell (PBMC) transcriptomic datasets of MeS and DMCAD were analyzed using an integrative bioinformatics approach. Differentially expressed genes (DEGs) were identified using the limma package, followed by functional enrichment, protein–protein interaction (PPI) network construction, weighted gene co-expression network analysis (WGCNA), gene set enrichment analysis (GSEA), and miRNA regulatory network analysis. Candidate genes were further evaluated using an independent type 2 diabetes mellitus (T2DM) dataset for external transcriptomic validation. Integrated analyses identified immune-inflammatory and immuno-metabolic pathways as central features of both MeS and DMCAD. Enrichment analyses highlighted cytokine signaling, leukocyte activation, chemotaxis, complement activation, oxidative stress, and vascular inflammatory responses. Network analyses identified CD86, CD33, CCR1, C5AR1, FPR1, CXCL16, and LILRA5 as key hub genes associated with immune regulation and cardiometabolic dysfunction. External transcriptomic validation supported the relevance of CD33, CD86, and LILRA5. miRNA network analysis identified members of the miR-17/92 family and miR-146a-5p as potential upstream regulators. TAM 2.0 enrichment analysis further linked these miRNAs to metabolic syndrome, diabetes mellitus, atherosclerosis, coronary heart disease, immune response, inflammation, and angiogenesis. Our findings suggest that coordinated immune-inflammatory and metabolic signaling networks contribute to the progression from MeS to DMCAD. The identified hub genes and miRNAs may serve as potential biomarkers and therapeutic targets for inflammation-driven cardiometabolic disease. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine. Full article

Microalgae–fungal pellets have been studied as a versatile and robust biotechnological platform, offering significant advantages for microalgal biomass harvesting, wastewater treatment, biofuels production and/or obtaining of value-added products. This review presents an integrated analysis of the mechanisms governing the formation, stability, and functionality of these systems, combining physicochemical, biological, and mathematical modelling approaches and aims to describe the current state of the art and main research needs. The aggregation process is strongly influenced by the complementarity of the surface properties of microalgae and filamentous fungi, including electrostatic interactions, production of extracellular polymeric substances (EPSs), and modifications in surface roughness. Recent advances in multiscale characterization techniques, such as confocal microscopy, micro-computed tomography, atomic force microscopy, and X-ray photoelectron spectroscopy, have allowed a more precise elucidation of the internal architecture and surface chemistry of the pellets. In parallel, biological characterization through enzymatic assays, oxidative stress biomarkers, and photosynthetic activity analyses has provided relevant information on the metabolic responses and functional resilience of the consortium. Additionally, the incorporation of mathematical flocculation models can contribute to the prediction of pellet growth, density, and stability, supporting process optimization and application. The understanding of these interaction phenomena is important for the design of high-yield and efficient systems, including their development and validation, to expand the use of microalgae–fungal pellets in bioprocesses, as evidenced by this review. Full article

Background: Competitive sports represent a powerful physiological and psychological stressor capable of modulating neuroendocrine and immune pathways. Water polo, characterized by intense intermittent exertion and frequent physical contact, provides a unique model to investigate competition-related stress biology. Methods: Sixteen male Italian Serie C water polo players were enrolled in the study. Using a within-subject design, saliva samples were collected under controlled circadian conditions. Salivary biomarkers, including cortisol, IgA, and cytokines, were assessed both before and after training sessions and competitive matches. Results: Both training and competition elicited POST-session increases in salivary cortisol and cytokines, alongside reductions in IgA. However, competition produced significantly higher anticipatory and POST-session cortisol concentrations. A larger POST-session decreases in IgA compared with training was observed. Cytokine concentrations increased from PRE- to POST-session in both conditions, with significantly greater induction during competition across the panel. During training, selected cytokines showed positive within-session correlations with cortisol, indicating coordinated hypothalamic–pituitary–adrenal–immune activation under lower psychosocial load. These associations were attenuated and less consistent during competition. Conclusions: Official competition amplifies endocrine and immune responses beyond those observed during match-like training in elite water polo players, despite comparable physical demands. Altered cytokine–cortisol coupling under competitive conditions suggests modulation of neuroendocrine–immune integration by psychosocial stress. Combined salivary profiling of cortisol, cytokines, and IgA represents a feasible, non-invasive approach for monitoring psychophysiological load in elite aquatic team sports. Full article

Chronic wounds represent a substantial and growing clinical burden, yet durable healing remains difficult to achieve in a large proportion of patients. The skin microbiome plays a central role in this challenge: in healthy tissue, resident microorganisms support barrier integrity and calibrate immune responses, whereas in chronic wounds, community disruption—often combined with persistent biofilm formation—drives non-resolving inflammation, impairs re-epithelialisation, and increases antimicrobial tolerance. As antibiotic resistance escalates, these features strengthen the rationale for microbiome-directed strategies that target wound ecology while reducing reliance on conventional antimicrobials. Current evidence is still dominated by mechanistic and preclinical studies, with only early clinical signals for selected approaches; therefore, next-generation probiotics, including Lactiplantibacillus/Lactobacillus spp., as well as defined prebiotic and postbiotic formulations, should be interpreted as promising adjuncts rather than clinically established therapies. Causal mechanisms, optimal formulations, reproducibility, and patient-level determinants of response remain insufficiently defined, representing a critical knowledge gap that limits translation. Here, we synthesise current evidence linking microbial ecology to key wound-healing pathways and propose a precision framework that integrates metagenomics, transcriptomics, metabolomics, and spatial profiling to map host–microbe interactions, identify predictive biomarkers, and guide stratified therapy. We further highlight combinatorial approaches pairing ecological engineering with biofilm-disruptive materials and immune-modulatory molecules. Realising the potential of these interventions will require mechanism-resolved clinical trials, standardised outcome frameworks, and patient stratification tools—advances that could improve chronic wound management while reducing selective pressure for antimicrobial resistance. Full article

The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial–lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling. Full article